In recent years photochemoprevention has matured into an accepted modality for controlling skin cancer. Although photochemoprevention can be achieved by intervention at initiation or promotion phases of skin tumorigenicity, for a variety of reasons, for example availability of sunscreens to prevent penetration of ultraviolet (UV) radiation, anti-tumor promoting agents appear to have greater likelihood for success in human. However, the search for ideal agent(s) for the armamentarium of photochemoprevention continues. Plant-based flavonoids, a group of polyphenolic compounds, are showing promise as useful chemo- preventive and chemotherapeutic agents. Pomegranate fruit extract (PFE), derived from the tree of Punica granatum, is a rich source of two types of polyphenolic compounds; anthocyanins and hydrolyzable tannins, and possesses potent antioxidant and anti-inflammatory properties. Recently we have demonstrated that topical application of PFE prevents chemically induced skin carcinogenesis. More recently, we found that the treatment of normal human epidermal keratinocytes (NHEK) with PFE inhibits DVB-mediated degradation and phosphorylation of IkappaBalpha, activation of IKKalpha and NFkappaB. In light of these data and other published studies there is a strong possibility that PFE or constituent(s) present therein may be developed as a novel photochemopreventive agent. The central hypothesis to be tested in this proposal is that PFE will afford protection against the development and progression of UVB-mediated photocarcinogenesis by blocking UVB-mediated ornithine decarboxylase (ODC) induction and by reducing NFkappaB activation. To test our hypothesis we will employ SKH-1 hairless and ODC overexpressing mouse models of photocarcinogenesis both of which appears to have relevance to human skin cancer. To accomplish our goals three specific aims are proposed: (i) to determine the effect of oral feeding of PFE on UVB-mediated modulation in cancer chemopreventive targets viz. ODC and NFkappaB pathway, and short-term markers of tumor promotion in SKH-1 hairless mice, (ii) to establish the preventive potential of PFE against UVB-mediated skin tumorigenesis in SKH-1 hairless mice and, (iii) to study the effect of oral feeding of PFE on UVB-initiated skin tumorigenesis in ODC overexpressing mice. HEALTH RELEVANCE: This proposal intends to define a novel photochemo- preventive agent against skin cancer for its possible use in humans.